Radiation sensitizer or anti-cancer chemotherapy sensitizer

ABSTRACT

The present invention provides a novel radiosensitizer or anti-cancer chemotherapy sensitizer. In particular, the invention provides a radiosensitizer or anti-cancer chemotherapy sensitizer that can relieve the irritation of an affected area caused by hydrogen peroxide, is safe when injected into a human body, and can delay or reduce the degradation of hydrogen peroxide and thereby can efficiently exert a radiation sensitizing effect and an anti-cancer chemotherapy sensitizing effect. The radiosensitizer or anti-cancer chemotherapy sensitizer comprises a combination of (a) hydrogen peroxide and (b) hyaluronic acid or salt thereof.

TECHNICAL FIELD

This invention relates to a radiosensitizer or anti-cancer chemotherapysensitizer, particularly to a radiosensitizer or anti-cancerchemotherapy sensitizer (injection composition for radiosensitizer orchemotherapy sensitizer application) applied to or injected into a tumorarea prior to irradiation or anti-cancer chemotherapy (administration ofanti-cancer agent). It also relates to anti-cancer therapy using theradiosensitizer or anti-cancer chemotherapy sensitizer of the invention.

BACKGROUND ART

Radiotherapy is second to surgical operations as a method of locallytreating malignant tumors. Because it can be applied to elderly patientsand also enables normal organs and tissues to be conserved, the numberof patients being treated by the method is recently increasing veryrapidly. However, linear accelerator-generated high-energy X-rays andelectron beams that are generally used for the radiotherapy are lowlinear energy transfer (LET) radiation having a relatively lowbiological effect. Accordingly, linear accelerator based radiotherapyhas little effect on tumors such as malignant melanoma, various types ofsarcoma and glioblastoma multiforme and the like. Also, because locallyadvanced neoplasms that have grown to several centimeters or more havemany hypoxic cancer cells or contain large amounts of anti-oxidativeenzyme, and are therefore resistant to radiation, linear acceleratorbased radiotherapy has little effect.

Heavy particle beam therapy is a method used to improve theradiotherapeutic effect on these. However, the widespread use of heavyparticle beam therapy is made difficult due to the large cost of theequipment, which involves an investment of several tens of billions ofyen.

Since before, various radiosensitizers (such as, for example,Metronidazole, Misonidazole, Etanidazole, Nimorazole, and so forth) havebeen developed to increase the radiotherapeutic effect (see non-patentdocuments 1 to 3, for example). However, in addition to the uncertaintyof their effect, they have side effects such as peripheral neuropathyand the like, and therefore are not yet allowed to be used in clinicalpractice.

Using radioresistant osteosarcoma cell lines (HS-Os-1), the presentinventors previously confirmed that sensitivity to the radiation effectcould be increased and apoptosis readily induced by adding a lowconcentration of hydrogen peroxide to a culture solution during theirradiation. Normally, such radioresistant osteosarcoma cells orchondrocytes suffer little DNA oxidative damage even when exposed toradiation of 30 Gy. In contrast, when irradiated in the presence of alow concentration (0.1 mM, for example) of hydrogen peroxide, reactiveoxygen species can be clearly produced in cells exposed to radiation inthe order of 10 Gy, giving rise to apoptosis. One cause that can becited for the radiation resistance of osteosarcoma cells is the presenceof anti-oxidative enzyme (peroxidase, catalase) in the cells. Hydrogenperoxide is thought to block the action of the anti-oxidative enzyme.That is, when irradiation is conducted in the presence of hydrogenperoxide, the action of the anti-oxidative enzyme is blocked and oxygenis produced, oxidizing the radioresistant hypoxic cells, therebyconverting them to being highly sensitive to radiation (see, forexample, non-patent documents 4 to 6).

Non-patent document 1: Chapman J D, Whitmore G F (eds): Chemicalmodifiers of cancer treatment. Int J Radiat Oncol Biol Phys 10:1161-1813, 1984.

Non-patent document 2: Coleman C N.: Hypoxic cell radiosensitizers:Expectations and progress in drug development. Int J Radiat Oncol BiolPhys 11: 323-329, 1985.

Non-patent document 3: Radiobiology for the Radiologist (Sixth Edition)by Eric J. Hall and Amato J. Giaccia, Lippincott Williams & Wilkins,419-431, 2006.

Non-patent document 4: Yasuhiro Ogawa et al.: Mechanism of apoptoticresistance of human osteosarcoma cell line, HS-Os-1, againstirradiation. International Journal of Molecular Medicine 12: 453-458,2003.

Non-patent document 5: Yasuhiro Ogawa et al.: Apoptotic-resistance ofhuman osteosarcoma cell line HS-Os-1 to irradiation is converted toapoptotic-susceptibility by hydrogen peroxide: A potent role of hydrogenperoxide as a new radiosensitizer. International Journal of MolecularMedicine 12: 845-850, 2003.

Non-patent document 6: Yasuhiro Ogawa et al.: Immunocytochemicalcharacteristics of human osteosarcoma cell line HS-Os-1: Possibleimplication in apoptotic resistance against irradiation. InternationalJournal of Molecular Medicine 14: 397-403, 2004.

DISCLOSURE OF THE INVENTION

Based on the finding that hydrogen peroxide has the radiosensitizationeffect on osteosarcoma cell line as described above, the presentinventor used sterilized cut cotton soaked in a hydrogen peroxidesolution having a concentration of approximately 3 weight percent as abolus for a case of inoperable locally advanced malignant melanoma(superficially-exposed carcinoma) which was then subjected toirradiation by an electron beam from a linear accelerator. Radiation wasconducted three times a week, with each radiation dose amounting to 4Gy, for a total radiation dose of 48 Gy, resulting in the good effect ofthe disappearance of the tumor (Reference Example 1).

However, hydrogen peroxide solution (or the hydrogen peroxide dilutedwith distilled water) is a strong irritant that should not be applieddirectly in a large quantity to an affected part, and further, its useis contraindicated where there is a risk that the hydrogen peroxidesolution could seep into a body cavity such as in the case of a fistulaor contused wound. Also, hydrogen peroxide is unstable, and when appliedto the affected part immediately starts releasing oxygen, so that if itwere to be injected as is subcutaneously or into human tissue, such as atumor, there is a danger that it will be rapidly degraded into water andoxygen by the action of anti-oxidative enzymes, such as peroxidase andcatalase, and cause complications such as pulmonary embolism. For thatreason, there is a need for a pharmaceutical invention that canalleviate the irritation of hydrogen peroxide so that it can be appliedto fistula or contused wounds or the like, or safely injected into thehuman body, and that also delays and suppresses the degradation of thehydrogen peroxide.

An object of the present invention is to provide a radiosensitizer oranti-cancer chemotherapy sensitizer that is devised to enable theradiosensitizer and anti-cancer chemotherapy sensitizer effect to beefficiently exerted by relieving the irritation that hydrogen peroxidehas on an affected area, can be safely injected into the human body, andcan delay or reduce the degradation of the hydrogen peroxide.

Means for Solving the Problems

Through diligent study aimed at solving the above problems, it was foundthat the irritation of hydrogen peroxide on the skin as well as theirritation with respect to mucous membranes and tissues could be reducedby combining hyaluronic acid or a salt thereof with the hydrogenperoxide. Moreover, it was found that by combining hyaluronic acid or asalt thereof with the hydrogen peroxide, the tendency of the hydrogenperoxide to readily give off oxygen due to its instability can bereduced, and even when it is injected into the human body, the rapiddegradation of the hydrogen peroxide due to the action of anti-oxidativeenzymes is significantly reduced, enabling the radiation sensitizingeffect and anti-cancer chemotherapy sensitizing effect to be exertedmore safely and efficiently.

The present invention was accomplished based on the above findings, andis characterized by having the following composition.

(I) Radiosensitizer or Anti-Cancer Chemotherapy Sensitizer

(I-1) A radiosensitizer or anti-cancer chemotherapy sensitizercomprising a combination of (a) hydrogen peroxide and (b) hyaluronicacid or a salt thereof.

(I-2) A radiosensitizer or anti-cancer chemotherapy sensitizer describedin (I-1) that is in a form of a combination preparation of (a) componentand (b) component mixed beforehand.

(I-3) A radiosensitizer or anti-cancer chemotherapy sensitizer describedin (I-1) that is used in a form in which (a) component and (b) componentare mixed at time of use. Said form includes a kit having at least (a) aformulation containing hydrogen peroxide and (b) a formulationcontaining hyaluronic acid or a salt thereof.

(I-4) A radiosensitizer or anti-cancer chemotherapy sensitizer describedin any of (I-1) to (I-3) that has the form of an injection or may beused as an injection.

(I-5) A radiosensitizer or anti-cancer chemotherapy sensitizer describedin any of (I-1) to (I-4) in which the hydrogen peroxide content in thefinal formulation is 0.01 to 3.5 weight percent.

(I-6) A radiosensitizer or anti-cancer chemotherapy sensitizer describedin any of (I-1) to (I-5) in which the content of the hyaluronic acid ora salt thereof in the final formulation is 0.1 to 10 weight percent.

(I-7) A radiosensitizer or anti-cancer chemotherapy sensitizer describedin any of (I-1) to (I-6) that may be used by intratumoral injection intothe area that is resistant to radiotherapy or resistant to anti-cancerchemotherapy.

(I-8) A radiosensitizer or anti-cancer chemotherapy sensitizer describedin any of (I-1) to (I-7) that is used on a tumor area prior toirradiation or anti-cancer chemotherapy in a case of radiotherapy of aradioresistant tumor or anti-cancer chemotherapy of an anti-cancerchemotherapy resistant tumor.

(I-9) A radiosensitizer described in (I-8) in which the irradiation isperformed using an X-ray beam or electron beam from a linearaccelerator.

(II) Radiotherapy Sensitizing Method or Anti-Cancer ChemotherapySensitizing Method.

(II-1) A radiotherapy or anti-cancer chemotherapy sensitizing methodhaving a step of processing of a tumor area by the radiosensitizer oranti-cancer chemotherapy sensitizer described in any of (I-1) to (I-6),at the same time as or prior to irradiation or anti-cancer chemotherapyin the course of radiotherapy or anti-cancer chemotherapy of a tumor.

(II-2) The sensitizing method described in (II-1) in which the tumor isa tumor that is resistant to radiotherapy or resistant to anti-cancerchemotherapy.

(II-3) The sensitizing method described in (II-1) or (II-2) in which theprocessing is an intratumoral injection of the radiosensitizer oranti-cancer chemotherapy sensitizer described in any of (I-1) to (I-6).

(II-4) The sensitizing method described in any of (II-1) to (II-3) inwhich the irradiation is performed using an X-ray beam or electron beamfrom a linear accelerator.

(II-5) A sensitizing method described in any of (II-1) to (II-3) inwhich the anti-cancer chemotherapy is an administration of ananti-cancer agent to a patient.

(III) Radiosensitization Method or Anti-Cancer ChemotherapySensitization Method

(III-1) A radiosensitization method or anti-cancer chemotherapysensitization method comprising

-   (1) a step of processing a tumor area with the radiosensitizer or    anti-cancer chemotherapy sensitizer of any of (I-1) to (I-6), and-   (2) a step of exposing the processed tumor area to irradiation or    the patient to anti-cancer chemotherapy.

(III-2) A radiosensitization method or anti-cancer chemotherapysensitization method described in (III-1) in which the tumor is a tumorthat is resistant to radiotherapy or resistant to anti-cancerchemotherapy.

(III-3) A radiosensitization method or anti-cancer chemotherapysensitization method described in (III-1) or (III-2) in which theprocessing is an intratumoral injection of the radiosensitizer oranti-cancer chemotherapy sensitizer described in any of (I-1) to (I-6).

(III-4) A radiosensitization method or anti-cancer chemotherapysensitization method described in any of (III-1) to (III-3) in which theirradiation is irradiation by an X-ray beam or electron beam produced bya linear accelerator.

(III-5) A radiosensitization method or anti-cancer chemotherapysensitization method described in any of (III-1) to (III-3) in which theanti-cancer chemotherapy is an administration of an anti-cancer agent tothe patient.

(IV) Use for Sensitizing Radiotherapy or Sensitizing Anti-CancerChemotherapy

(IV-1) Use of a radiosensitizer or anti-cancer chemotherapy sensitizerdescribed in any of (I-1) to (I-6) for sensitizing radiotherapy or forsensitizing anti-cancer chemotherapy.

(V) Method of Alleviating Pain of Radiosensitizer or Anti-CancerChemotherapy Sensitizer

(V-1) A method of alleviating pain of the radiosensitizer or anti-cancerchemotherapy sensitizer in the tumor area characterized by combining (a)hydrogen peroxide and (b) hyaluronic acid or a salt thereof.

EFFECT OF THE INVENTION

In accordance with the radiosensitizer and radiosensitization methodusing the same of this invention, it is possible to obtain a superiorradiotherapeutic effect using low-LET beams, even with respect toradioresistant tumors because they contain many hypoxic cells.

Also, the anti-cancer chemotherapy sensitizer of the invention increasesthe effect of the anti-cancer chemotherapy (anti-cancer drug treatment)by inactivating anti-oxidative enzymes in the tumor region. Thus, inaccordance with the anti-cancer chemotherapy sensitization method ofthis invention in which the anti-cancer chemotherapy sensitizer of theinvention is combined with anti-cancer chemotherapy, it is possible toobtain a superior anti-cancer treatment effect even with cancers thatare intractable to anti-cancer chemotherapy.

BEST MODE FOR CARRYING OUT THE INVENTION

The radiosensitizer or anti-cancer chemotherapy sensitizer of thepresent invention is characterized by comprising a combination of (a)hydrogen peroxide and (b) hyaluronic acid or a salt thereof.

The radiation and anti-cancer chemotherapy sensitizer according to theinvention is a pharmaceutical compound that can be used on a tumor areaprior to, or simultaneously with, radiotherapy (irradiation) as well asanti-cancer chemotherapy, to strengthen the effect that radiotherapy andanti-cancer chemotherapy has on the tumor area.

In this invention, “anti-cancer chemotherapy” means all treatments basedon anti-cancer agents (carcinostatic agents). Linear accelerator basedradiotherapy of cancer cells has around a 70% dependency on theproduction of reactive oxygen species such as hydroxyl radicals. Themechanisms of various anti-cancer agents (carcinostatic agents) havethis point in common. Therefore, a substance that increases thesensitivity of the radiotherapy effect at the same time increases thesensitivity of the anti-cancer chemotherapy effect.

The hyaluronic acid used by the invention may be derived from anysource; it may be extracted from animal tissues or manufactured by afermentation method. For safety and manufacturing stability, it ispreferably manufactured by a fermentation method. There is no particularlimitation on the strain used in the fermentation method, any hyaluronicacid producing microorganism desired being usable, such as, for example,a hyaluronic acid producing organism isolated from nature that belongsto a genus such as Streptococcus, the Streptococcus equi FM-100described in JP63-123392A (Fermentation Research Institute BacillusDeposit No. 9027) or the Streptococcus equi FM-300 described inJP2-234689A (Fermentation Research Institute Bacillus Deposit No. 2319).

Heretofore, hyaluronic acids having various molecular weights have beenknown. While it is not a limitation, the present invention can usehyaluronic acid having a molecular weight normally about 500000 to about10 million, preferably about 500000 to about 8 million, and morepreferably about 500000 to about 5 million.

The weight average molecular weight of the hyaluronic acid can bemeasured by the SEC-MALLS method comprising using a size-exclusionchromatogram (SEC) coupled to a multi-angle laser light-scatteringdetector (MALLS) (see, for example, C. Yomota, Bull. Natl. Inst. HealthSci., 121, 030-033 (2003)).

The hyaluronic acid that is an object of the invention may becrosslinked hyaluronic acid. Here, crosslinked hyaluronic acid is amacro-molecule having a three-dimensional mesh structure that forms agel that swells in the medium. That is, crosslinked hyaluronic acid hasa hydrogel morphology that swells in a physiologically permissiblemedium.

As an example of a crosslinked hyaluronic acid, there can be mentioned acrosslinked hyaluronic acid formed from a hyaluronic acid having aweight average primary molecular weight that is greater than 800000. Thecrosslinked hyaluronic acid is characterized in that, when it is severedat the crosslink point, it forms a straight-chain hyaluronic acid havinga weight average molecular weight that is greater than 800000. Thedegree of branching and the weight average molecular weight of thehyaluronic acid produced by cutting at the crosslink point can bereadily measured by GPC-MALLS (multi-angle light scattering) using amulti-angle laser light-scattering detector (MALLS) and a differentialrefractive index detector with a gel permission chromatogram (GPC).

The crosslinked hyaluronic acid used by the invention may be one inwhich the crosslink point is hydrolyzable. Here, a crosslink point thatis hydrolyzable means one wherein, under physiological conditions suchas at 37° C. and a pH of 7.4, in a physiological saline solution, thecrosslink point is apt to degrade before the main chain of thehyaluronic acid. While crosslink structures having a hydrolyzabilitythat is superior to the main chain degradation of the hyaluronic acidthat can be cited include carbamate bonds, hydrozone bonds, hydrazidebonds, phosphate and ester bonds, the most typical structures are esterbonds.

Examples of crosslinked hyaluronic acids having an ester bondcrosslinked structure include esters of carboxyl group of hyaluronicacid and polyhydric alcohol, esters of hydroxyl group of hyaluronic acidand polyhydric carboxylic acid, esters of carboxyl group of hyaluronicacid and polyhydric epoxide, and so forth. The crosslinked hyaluronicacid concerned includes a crosslinked hyaluronic acid in which there isa direct ester bond between the carboxyl group and the hydroxyl group ofthe hyaluronic acid (called a bridge ester having a self-crosslinkedester bond, or a hyaluronic acid having a self-crosslinked ester bond).

A hyaluronic acid having self-crosslinked ester bonds can bemanufactured by methods that are public knowledge. For example, asdescribed in EP 0341745 B1, a hyaluronic acid having self-crosslinkedester bonds can be manufactured by esterifying a part or all of thecarboxyl groups with the alcoholic functions of the same polysaccharidechain or other polysaccharide chains; or by the method described by WO99/10385 in which a solution of a hyaluronic acid is acidified, and thesolution is frozen and thawed at least once to thereby prepare ahyaluronic acid having self-crosslinked ester bonds; or by the methoddescribed in WO 01/57093, in which without freezing, a hyaluronic acidand an acidic solution are mixed together to produce a 5% or higherconcentration and the state of coexistence is maintained to therebyprepare a hyaluronic acid having self-crosslinked ester bonds.

Because the natural hyaluronic acid emitted by hydrolysis of thehyaluronic acid having self-crosslinked ester bonds is metabolized byphysiological metabolic pathways, it is considered to be safer than acrosslinked hyaluronic acid manufactured by other crosslinkingreactions.

As a crosslinked hyaluronic acid, there can be mentioned a hyaluronicacid in which the carboxyl group of the hyaluronic acid is crosslinkedto the hydroxyl group of the same hyaluronic acid molecules, and/or tothe hydroxyl group of different hyaluronic acid molecules (see, forexample, JP 2003-252905 A).

The degree of crosslinking of a crosslinked hyaluronic acid, forexample, the amount of intermolecular ester bonding of the molecules tobe introduced, can be arbitrarily controlled according to the purpose ofthe crosslinked hyaluronic acid or the required properties thereof. Theamount of ester bonding can be defined as the ratio to the total numberof carboxyl groups in the hyaluronic acid. In the radiosensitizer oranti-cancer chemotherapy sensitizer of this invention, the hyaluronicacid is preferably used as a water solution or a water swelling gel.When the hyaluronic acid is used in the form of a water solution, whilethere is no limitation, it is preferable to use a crosslinked hyaluronicacid in which the amount of intermolecular ester bonding is less than0.5%. Also, when the hyaluronic acid is used as a water swelling gel,while there is no limitation, it is preferable to use a crosslinkedhyaluronic acid in which the amount of intermolecular ester bonding isabout 0.5% to about 1%. The molecular structure of the crosslinkedhyaluronic acid can be confirmed by using NMR (Carbohydr. Res. Vol 245,p 113-128, 1993; Macromolecules Vol 29, p 2894-2902, 1996).

A crosslinked hyaluronic acid can be prepared by, for example,acidifying a water solution of hyaluronic acid and converting thedissociated carboxyl groups to the acid form. Because underhigh-temperature conditions an N-acetyl-D-glucosamine unit deacetylationreaction is produced that competes with the crosslinking reaction, it isdesirable to reduce the reaction temperature of the process used toacidify the hyaluronic acid water solution (see JP H1-266102 (A)). Thereaction temperature used to give precedence to crosslink formation ispreferably not higher than room temperature, and is more preferably notmore than 10° C. Also, to promote the intermolecular esterificationreaction, it is preferable to raise a hyaluronic acid concentration. Forexample, the hyaluronic acid concentration of the reaction solution ispreferably 5 weight percent or above, and more preferably 10 weightpercent or above. Also, the intermolecular esterification reaction canbe promoted by adding to the reaction system a substance that catalyzesthe dehydration-condensation reaction. An acidic catalyst is commonlyused as a catalyst for promoting the dehydration-condensation reaction,for which sulfuric acid, hydrochloric acid or a sulfonic acid derivativeof an aromatic compound or the like may be used.

When the crosslinked hyaluronic acid is being formed, it may be mixed orcompounded with materials having the same good biocompatibility as thehyaluronic acid, for example, chondroitin sulfate,carboxymethyl-cellulose, and so forth. It is also possible to addpharmacologically or physiologically active substances to form acrosslinked hyaluronic acid containing such substances.

The crosslinked hyaluronic acid thus obtained can next be subjected toan operation to adjust the acidity by removing acid components. Thisremoval of acid components is normally performed in a water solvent by,for example, washing or dialyzing. There is no particular limitation onthe water solvent that may be used, provided it does not impair thefunction of the crosslinked hyaluronic acid. Examples of the usablewater solvents include water, physiological saline, a phosphoric acidbuffer solution and so forth, but it is preferable to use physiologicalsaline or a phosphoric acid buffer solution and the like. When acid formcarboxyl groups remain after the crosslinked hyaluronic acid has beenwashed, they can be formed into a salt of sodium or the like(salification). There is no particular limitation on the salificationmethod used, and applicable methods include, for example, using a watersolution of sodium hydroxide to adjust the crosslinked hyaluronic acidsolution to a pH of around 7, or immersing the crosslinked hyaluronicacid in physiological saline or a phosphoric acid buffer physiologicalsaline solution.

Depending on the purpose, the crosslinked hyaluronic acid thus preparedmay be used in solution form, in the solvent immersion state, or in amoist state that includes the solvent, as the material of theradiosensitizer or anti-cancer chemotherapy sensitizer of the invention(hereinafter also referred to simply as “the sensitizer”).

The crosslinked hyaluronic acid swells to a gel in a physiologicallypermissible medium. Therefore, when the sensitizer of the invention isused as an injection, in order to inject it through a needle into thearea of the tumor to be subjected to irradiation or anti-cancerchemotherapy, it is necessary for the crosslinked hyaluronic acid (gel)to be dispersed as a suspension in a physiologically permissible medium.The suspension may be prepared by crushing the crosslinked hyaluronicacid at either the manufacturing or refining process stage thereof,using a crusher such as a mixer or homogenizer. The diameter of thehydrogel particles may be arbitrarily adjusted. However, after thecrosslinked hyaluronic acid has been dispersed in the physiologicallypermissible medium and homogenized, the dispersion particle diameter canbe readily adjusted normally from about 0.05 to about 2 μm.

The equilibrium swelling ratio of the crosslinked hyaluronic acid gelcan be adjusted arbitrarily according to the degree of crosslinking ofthe crosslinked hyaluronic acid. For example, in the case of anequilibrium swelling ratio of 100 times, the concentration of thehyaluronic acid in the physiologically permissible medium will be 1%. Inthe case of an equilibrium swelling ratio of 10 times, the concentrationof the hyaluronic acid in the physiologically permissible medium will be10%.

In the sensitizer of this invention, as mentioned in the foregoing, anordinary hyaluronic acid (non-crosslinked), a crosslinked hyaluronicacid, or an arbitrary combination thereof may be used. A hyaluronic acidin a single form or a hyaluronic acid of a single molecular weight mayalso be used. Further, various crosslinked hyaluronic acids orhyaluronic acids of various molecular weights may be used incombination.

In the sensitizer of this invention, a hyaluronic acid (as a generalconcept that includes a crosslinked hyaluronic acid) may be used in theform of a salt. Suitable examples of hyaluronic acid salts are, but arenot limited to, alkali metal salts such as sodium, potassium, lithium,and so forth. A sodium salt of hyaluronic acid is preferable.

The proportion of hyaluronic acid or a salt thereof contained in thesensitizer of the invention (the final formulation) is not limited, andmay be selected from the range of 0.1 to 10 weight percent. 0.1 to 5weight percent is preferable, and 0.1 to 3 weight percent is morepreferable.

According to the sensitizer of the invention, at least one memberselected from the group consisting of liposomes, polymer gels andgelatins may be used in place of the above hyaluronic acid or a saltthereof, or in combination therewith.

Here, a liposome refers to a multilayer capsule structure formed of aphospholipid. Preferably, the liposome is hollow. Using the liposomeenables the radiosensitizer or anti-cancer chemotherapy sensitizer to beprepared as a liposome formulation in which a hydrogen peroxide solutionis encapsulated by the membrane of a phospholipid microparticle orwithin a phospholipid microparticle. Such a liposome formulation can bereadily prepared by adding a hydrogen peroxide solution into the hollowliposome (at a temperature of, for example, about 16 to about 40° C.),and then softly stirring by rotating the resulting product by hand 3 to5 times. Liposomes are commercially available, examples being theEVTRASOME (trademark) series (NOF Corporation) and the Cortosome ELseries (Funakoshi Corporation).

The proportion of liposomes contained in the sensitizer of the invention(the final formulation) is not limited, and may be suitably selectedfrom the range of 0.01 to 10 weight percent.

For a polymer gel, the polymer gels disclosed in the publication ofHaaga et al. (Combined tumor therapy by using radiofrequency ablationand 5-FU-laden polymer implants: evaluation in rats and rabbits.Radiology 237: 911-918, 2005) may be used.

The proportion of polymer gel contained in the sensitizer of theinvention (the final formulation) is not limited, and may be suitablyselected from the range of 0.01 to 10 weight percent.

With respect to gelatin, there is no particular limitation as long as itis one that can be applied to the human body such as for medical orcosmetic use or for edible use. A gelatin for medical applicationdefined by a pharmacopeia is preferable. Such gelatins are widelyavailable commercially, for example, a porous gelatin (trade name:“Gelpart,” Astellas Pharma Inc.) sold as an intravascularemboli-promoting prosthetic material.

The proportion of gelatin contained in the sensitizer of the invention(the final formulation) is not limited, and may be suitably selectedfrom the range of 0.01 to 5 weight percent.

The sensitizer of the invention is characterized by comprising acombination of at least one of the aforementioned components (alsoreferred to in the invention as “(b) component”) and hydrogen peroxide(also referred to in the invention as “(a) component”). Preferably, thecombination is of a hyaluronic acid or a salt thereof ((b) component)and hydrogen peroxide ((a) component).

Here, “a combination” is used to inclusively mean the sensitizer of theinvention that is used

(i) in a state in which both the (a) component and the (b) component areincluded from the beginning (combination preparation);

(ii) for sale as a combination (a kit) including a separately packagedformulation containing the (a) component and a separately packagedformulation containing the (b) component; or

(iii) in a formulation containing the (a) component and a formulationcontaining the (b) component that are separately packaged and are inseparate market distribution channels and are combined at time of use.

That is, in this invention, “radiosensitizer or anti-cancer chemotherapysensitizer comprising a combination” means that the radiosensitizer oranti-cancer chemotherapy sensitizer that is ultimately used (referred toin this invention as the “final formulation”) may include both the (a)component and the (b) component, with the form at the sales anddistribution stage being immaterial.

The proportion of the hydrogen peroxide used as the (a) component in thefinal formulation of the radiosensitizer or anti-cancer chemotherapysensitizer of the invention is not limited, and may be suitably selectedfrom the range of 0.01 to 3.5 weight percent. It is preferably 0.05 to 3weight percent, and more preferably 0.1 to 2 weight percent.

The composition ratio of the hyaluronic acid or a salt thereof to thehydrogen peroxide is not limited. The total amount of the hyaluronicacid or a salt thereof may be suitably selected from the range of 1 to10000 parts by weight per 100 parts by weight of hydrogen peroxide,preferably 10 to 1000 parts by weight, and more preferably 50 to 150parts by weight.

There is also no limitation on the composition ratio of the liposomes,polymer gel or gelatin to the hydrogen peroxide, which may be adjustedin accordance with the above-described examples of hyaluronic acid orsalts thereof. For example, the amount of liposomes may be suitablyselected from the range of 1 to 10000 parts by weight per 100 parts byweight of hydrogen peroxide, preferably 10 to 1000 parts by weight, andmore preferably 50 to 150 parts by weight. The amount of gelatin may besuitably selected from the range of 1 to 10000 parts by weight per 100parts by weight of hydrogen peroxide, preferably 10 to 1000 parts byweight, and more preferably 50 to 500 parts by weight.

In addition to the above (a) component and (b) component, the sensitizerof the invention may include medically permissible physiological saline,a phosphoric acid buffer solution (for example, sodium chloride, sodiumdihydrogen phosphate, and sodium dihydrogen phosphate, and the like).While there is no limitation on the humoral property of the sensitizerof the invention, provided it is compatible with the human body, it ispreferable to adjust the pH to a range of 6 to 8.5, and more preferablyto a range of 6.8 to 7.8.

The sensitizer of the invention is a liquid (including a solution,emulsion or suspension) or a gel, other than which there are noparticular limitations on how it is used (the usage). For example, whenthe sensitizer liquid or gel is an external preparation for use duringirradiation, prior to the irradiation, the sensitizer liquid or gel canbe applied by methods such as spraying or coating it directly onto thetumor area or adhering it thereto, or impregnating sterile cotton orgauze with the sensitizer for application to the tumor area to beirradiated during the irradiation.

When the sensitizer liquid or gel of the invention is an injection form,the injection can be directly intratumorally injected using a syringe orthe like or indirectly injected via an angiography catheter into thetumor area at time of the irradiation. In this case, the sensitizerliquid or gel of the invention can be injected into the target tumorarea using a syringe or angiography catheter, before, after or at thesame time as the administration of the anti-cancer agent. Specifically,it is preferable to use a syringe having a needle of about 21 gauge toperform the intratumoral injection guided by ultrasonographicexamination while observing the state of permeation of the sensitizerinto the tissue. The sensitizer can be delivered widely to the tissueunder ultrasonographic guidance to modify the depth and direction of theinjection needle. The dose of sensitizer administered to the tumor areawill differ depending on the size of the tumor and the administrationmethod. When, for example, it is intratumorally injected, the dose(injection amount) is normally about 1 to about 5 ml, and preferablyabout 3 ml.

Preferably, the radiosensitizer or anti-cancer chemotherapy sensitizerof the invention is in the form of an injection (a radiosensitizerinjection or anti-cancer chemotherapy sensitizer injection). Theinjection can be obtained by preparing an aqueous solution using waterfor injection (distilled water for injection, sterile water forinjection, etc.), an isotonizing agent, a pH adjustment, and a buffersolution and the like. The (a) component and the (b) component are addedto the resulting aqueous solution in the proportions of theabove-described range. The resulting mixture is placed in a containerand the container is then sealed, followed by sterilization using ahigh-pressure steam sterilization, autoclave sterilization or the like.It is also possible to prepare a sensitizer of the invention by suitablymixing a formulation containing the (a) component and a formulationcontaining the (b) component at time of use (a preparation of typeprepared just before use), using water for injection (distilled waterfor injection, sterile water for injection, etc.), if required.

Examples of usable isotonizing agents include sodium chloride, glycerin,glucose, polyethylene glycol, propylene glycol, D-mannitol, fructose,xylitol, sodium dihydrogen phosphate and sodium phosphate. Preferably,sodium chloride is used. As the pH adjustment, there may be usedhydrochloric acid or sodium hydroxide or the like. The pH is adjusted asdescribed above to a range of 6 to 8.5, and preferably to a range of 6.8to 7.8. Examples of the buffer solutions that can be used formaintaining the pH include phosphoric acid buffer solutions, tris buffersolutions and acetic acid buffer solutions. Preferably, a phosphoricacid buffer solution is used.

As described in the above, in radiotherapy, the radiosensitizer of theinvention is used on a tumor area prior to irradiation. It can bepreferably used in radiotherapy of tumors that are radioresistant.

Examples of tumors that are radioresistant include tumors that have manyhypoxic tumor cells and tumors that have a lot of anti-oxidative enzyme.The biggest problem with cancer radiotherapy, which currently isconducted mainly with linear accelerators, is the presence ofradioresistant cancer cells. The radioresistant tumor tissues are mostlyin hypoxic regions and exhibit resistance to radiotherapy. In a hypoxicstate, the radiation-resistance of these cells' DNA damage induced bythe radiation is not fixed by oxygen. Moreover, reactive oxygen speciesproduced in the cancer cells by the radiation are eliminated byanti-oxidative enzymes, which is said to make it difficult to induceapoptosis. Specific examples of tumors that are radioresistant includemalignant melanomas, malignant glioblastomas and various types ofsarcomas such as osteosarcomas, as well as nearly all types of locallyadvanced neoplasms that have grown to several centimeters or more.

Radiotherapy using the radiosensitizer of the invention can beimplemented by first applying the radiosensitizer to the area of thetumor to be irradiated, and then preferably using a linear acceleratorto irradiate the affected part with X-rays or an electron beam. Whilethe X-ray conditions will differ depending on how far the tumor hasadvanced and its size and the like, a normal dose will be 1.5 to 3 Gy,preferably around 2 Gy, 2 to 5 times a week, and preferably 4 or 5 timesa week, over a period of 1 to 5 weeks, for a total dose of 20 to 70 Gy,preferably 40 to 70 Gy, and more preferably 50 to 60 Gy. While theelectron beam conditions will also differ depending on how far the tumorhas advanced and its size and the like, a normal dose will be 2 to 5 Gy,preferably around 4 Gy, 1 to 5 times a week, and preferably 2 or 3 timesa week, over a period of 1 to 5 weeks, for a total dose of 30 to 70 Gy,and preferably 40 to 60 Gy.

The anti-cancer chemotherapy sensitizer of the invention may be used onthe tumor area to be treated (preferably by injection), prior toanti-cancer chemotherapy (administration of anti-cancer agent).Preferably, it can be used on tumors that are difficult to treat withanti-cancer chemotherapy or which are relatively large. Many solidtumors exhibit resistance to anti-cancer chemotherapy, such as stomachcancer, non-small-cell lung cancer, colorectal and rectal cancer, livercancer, pancreatic cancer, uterine cancer and cancer of the esophagus.Nearly all locally advanced solid tumors are resistant to anti-cancerchemotherapy.

Anti-cancer chemotherapy using the anti-cancer chemotherapy sensitizerof the invention can be implemented in parallel with the administrationof anti-cancer agents (before, after or at the same time as theadministration of the anti-cancer agents), by applying the anti-cancerchemotherapy sensitizer of the invention to the target tumor area. Asdescribed above, the sensitizer is intratumorally injected preferablyusing a needle or a catheter guided by ultrasonographic examination.While the chemotherapy sensitizer injection conditions may differdepending on how far the tumor has advanced and its size and the like, amethod may be used in which normally each injection is from 1 ml to 5ml, preferably 3 ml, administered 1 to 5 times a month, preferably 1 or2 times every other week.

EXAMPLES

The invention will now be described in detail with reference to Examplesand Formulation Examples. However, the invention is not limited to theseexamples. In the following, also, unless otherwise specified the amountsof the components are expressed in weight percent. All of the treatmentsdescribed in the following examples were conducted with the approval ofthe ethics committee of Kochi Medical School and based on the wishes ofthe patients.

FORMULATION EXAMPLE 1

To 1 syringe (2.5 ml) of a hyaluronic acid preparation having a 1%concentration of sodium hyaluronate [(trade name: “ARTZ Dispo,” made bySeikagaku Corporation); 1 syringe (2.5 ml) of the preparation contains25 mg of sodium hyaluronate, 2.5 mg of L-methionine, sodium chloride,sodium hydrogenphosphate, crystalline sodium dihydrogen phosphate, andan isotonizing agent. The preparation is colorless, transparent viscousaqueous solution having a pH of 6.8 to 7.8, specific osmotic pressure of1.0 to 1.2 (relative to physiological saline) and a weight averagemolecular weight of 600000 to 1.2 million], 0.5 ml of a 3% solution ofhydrogen peroxide was added immediately before use, and mixed well toprepare the radiosensitizer or anti-cancer chemotherapy sensitizer ofthe invention. These sensitizers have a sodium hyaluronate concentrationof 0.83% and a hydrogen peroxide concentration of approximately 0.5%.This preparation was used in the following examples.

FORMULATION EXAMPLES 2 TO 7

The concentrations of the sodium hyaluronate and hydrogen peroxide inthe final formulations (Formulation Examples 2 to 7) of theradiosensitizer or anti-cancer chemotherapy sensitizer of the inventionare shown in the following Table 1.

The radiosensitizer or anti-cancer chemotherapy sensitizer can beprepared using the hyaluronic acid preparation (trade name: “ARTZDispo,” made by Seikagaku Corporation) and hydrogen peroxide used inFormulation Example 1.

TABLE 1 Formulation Formulation Formulation Formulation FormulationFormulation Example 2 Example 3 Example 4 Example 5 Example 6 Example 7Sodium 0.96 0.89 0.71 0.55 0.50 0.33 Hyaluronate Hydrogen 0.12 0.36 0.861.33 1.50 2.00 Peroxide

REFERENCE EXAMPLE 1

For a case of inoperable locally advanced malignant melanoma, sterilizedcut cotton soaked in a hydrogen peroxide solution having a concentrationof approximately 3 weight percent was used as a bolus, and irradiationby an electron beam from a linear accelerator (radiosensitizationtherapy) was then conducted.

Specifically, sterilized cut cotton soaked in a hydrogen peroxidesolution having a concentration of approximately 3% was applied to theaffected area of the locally advanced malignant melanoma as a bolus, andirradiation was conducted three times a week for four weeks, with eachradiation dose amounting to 4 Gy (12 times, for a total radiation dosageof 48 Gy). FIG. 1 shows the effect of the radiosensitization methodusing the hydrogen peroxide solution. As can be seen from the figure,the malignant melanoma, which was approximately 8 cm long before theradiotherapy (Pre-radiotherapy (RT)), had shrunk to a length ofapproximately 5 cm two weeks after termination of the radiotherapy (2weeks after RT), and at three months after termination of theradiotherapy, the tumor had been almost disappeared (3 months after RT).

EXAMPLE 1

(1) Mouse squamous epithelium cancer cells (SCCVII tumor cells) weretransplanted into the right leg of the same kind of C3H/He mouse(8-week-old female), and the following experiment was conducted when thetumor had grown to about 10 mm in diameter.

When a 27-gage thin needle was used to intratumorally inject 1 ml ofphysiological saline (pH 6.8) containing 0.5% hydrogen peroxide into thetumors of five mice, the mice were all observed to feel strong pain,violently resisting the injection. On the other hand, when a 27-gagethin needle was used to intratumorally inject 1 ml of the sensitizer ofFormulation Example 1 (pH 6.8) containing 0.5% hydrogen peroxide and0.83% sodium hyaluronate into the tumors of other five other mice, itwas observed that the pain of the injection was alleviated, with none ofthe mice becoming overly disturbed.

(2) Based on the above results, the following experiment was conductedon five normal volunteers.

When a 27-gage thin needle was used to subcutaneously inject 1 ml ofphysiological saline (pH 6.8) containing 0.5% hydrogen peroxide into theinside of the left arms of five normal volunteers, all complained ofsevere pain limited to the injection site that lasted about 1 hour. Onthe other hand, when a 27-gage thin needle was used to subcutaneouslyinject 1 ml of the sensitizer of Formulation Example 1 (pH 6.8)containing 0.5% hydrogen peroxide and 0.83% sodium hyaluronate into theinside of the right arms of five normal volunteers, all of thevolunteers felt almost no pain at the injection site.

The results of the above experiments show that the irritation caused byhydrogen peroxide can be alleviated by the coadministration of hydrogenperoxide and hyaluronic acid.

EXAMPLE 2

A radiosensitizer prepared by the method of Formulation Example 1 wasapplied to a case of a recurrent inoperable malignant fibroushistiocytoma (a large, 3 cm subcutaneous tumor on right femoral region),followed by electron beam irradiation by linear accelerator(radiosensitization therapy). In parallel, power doppler ultrasound wasused to measure blood flow signals in the tumor and the radiotherapeuticeffect was evaluated. The results are shown in FIG. 2.

The malignant fibrous histiocytoma was irradiated three times a week fortwo weeks, with each of the six doses being 4 Gy, for a total dosage of24 Gy, at which point abundant blood flow was observed in the tumor,showing that the radiotherapy had little effect (Figure: Recurrent MFH24 Gy). Then, 3 ml of radiosensitizer was intratumorally injected,followed by irradiation. When the irradiation was continued followingintratumorally injecting the radiosensitizer, the tumor blood flowsignals were observed to be considerably reduced (Figure: 36 Gy) at thetime the total dosage reached 36 Gy. When another 3 ml ofradiosensitizer was intratumorally injected followed by irradiation,there was a further reduction in the blood flow in the tumor (Figure: 48Gy) at the end of 48 Gy of radiotherapy. One week after the terminationof 48 Gy of radiotherapy, almost no blood flow signals could be observed(Figure: 1 week after 48 Gy), from which it was understood that thetumor had necrosed due to the radiosensitization method according to theinvention.

EXAMPLE 3

A radiosensitizer prepared by the method of Formulation Example 1 wasapplied to right axillary metastatic lymph nodes and to right supra- andinfra-clavicular metastatic lymph nodes in a case of breast cancer thatin addition to being inoperable was unaffected by anti-cancerchemotherapy, and X-ray irradiation by linear accelerator was performed(radiosensitization therapy). In parallel, computerized tomography (CT)images were obtained to evaluate the radiotherapeutic effect.

FIG. 3 on the left shows an image of the right side of the patient'schest, from the thorax to the neck region. FIG. 3 on the upper right isa coronal image of the part obtained by computerized tomography (CT).FIG. 3 on the lower right is a PET-CT frontal image of the patient. Inthe PET-CT image of FIG. 3 on the lower right, the reddened portions onthe lower right side and at the base of the neck on the right are thefoci (the brain is where the PET drug usually accumulates).

FIG. 4 on the upper left shows a CT image of the neck region prior toradiotherapy, and FIG. 4 on the lower left shows a CT image of the partbelow the right axilla prior to radiotherapy. A radiotherapy plannerdevice (Pinnacle 3) was used to plan linear accelerator X-rayradiotherapy of the neck region and below the right axilla, andtangential non-opposed quadrilateral portal radiation was conducted atuniformly distributed doses of 2.75 Gy for a total irradiation of 48.5Gy. The figures on the right side of FIG. 4 are CT images taken after 7irradiations (total dose of 19.25 Gy). However, radiosensitizationmethod using the radiosensitizer was conducted only for the rightaxilla, and not for the right neck portion. Specifically, irradiationwas conducted after the intratumoral injection of 3 ml ofradiosensitizer into the tumor of the right axilla (to implement 3sensitized radiation therapies at a rate of twice a week). Irradiationof the right neck portion was conducted without injecting aradiosensitizer.

FIG. 4 on the upper right is a CT image of the right neck portion takenafter irradiation of 19.25 Gy, and FIG. 4 on the lower left is a CTimage of the right axilla after irradiation of 19.25 Gy. As can be seenin FIG. 4 on the upper right, no change can be seen in the size of theright cervical lymphadenopathy that has been irradiated without beinginjected with the radiosensitizer. On the other hand, with respect tothe giant metastatic lymph nodes of the right axilla, the pre-radiationCT value of approximately 65 had decreased to approximately 24 when theirradiation amount reached 19.25 Gy. Also, from the image, it can beseen that necrosis has been induced (FIG. 4 on the lower right). Theseresults show that a pronounced radiosensitization effect is obtained byusing the radiosensitizer of the invention in combination with theradiotherapy.

EXAMPLE 4

With respect to the implementation of the widely-used anti-cancer ECchemotherapy (four drip infusions of 100 mg/m² of Epirubicinadministered in combination with 600 mg/m² of cyclophosphamide everythree weeks (four courses)) on two patients suffering from locallyadvanced breast cancers that were intractable to anti-cancerchemotherapy, just prior (2 or 3 hours) to the anti-cancer chemotherapy(administration of anti-cancer agent), 3 ml of an anti-cancerchemotherapy sensitizer prepared by the method of Formulation Example 1was intratumorally injected under ultrasonographic guidance. Fourcourses of anti-cancer chemotherapy sensitization were implemented, andthe existence and size of the tumors were confirmed by PET-CT at twoweeks after the 4 courses of anti-cancer chemotherapy sensitization.

PET-CT images of the patients taken before and after the anti-cancerchemotherapy sensitization are shown in FIGS. 5 and 6 respectively, withthe image on the left side in each figure being the PET-CT image beforethe anti-cancer chemotherapy sensitization, and the image on the rightside being the PET-CT image after the anti-cancer chemotherapysensitization. As can be seen from these, the breast cancer and axillarylymph nodes metastases (indicated by the arrows) have been disappearedby the anti-cancer chemotherapy sensitization of the invention.

These results show that a pronounced treatment sensitizer effect isobtained by using the anti-cancer chemotherapy sensitizer of theinvention in combination with the anti-cancer chemotherapy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of the radiosensitization method of a malignantmelanoma conducted in Reference Example 1. FIG. 1 at the upper left isan image showing the malignant melanoma area prior to radiotherapy, FIG.1 at the upper right is an image showing the malignant melanoma area atthe end of sensitized irradiation (48 Gy), FIG. 1 at the lower left isan image showing the malignant melanoma area two weeks after the end ofthe radiosensitization therapy, and FIG. 1 at the lower right is animage showing the malignant melanoma area three months after the end ofthe radiosensitization therapy.

FIG. 2 shows the effect of the radiosensitization method of a malignantfibrous histiocytoma conducted in Example 2. FIG. 2 on the upper-left isan image showing the blood-flow signals in the tumor after irradiation(total dose of 24 Gy) of the malignant fibrous histiocytoma withoutinjection of a radiosensitizer, FIG. 2 on the upper right and 2 on thelower left are images showing blood-flow signals in the tumor after thehistiocytoma is injected with a radiosensitizer and irradiated(upper-right FIG. 2: total dose of 36 Gy, lower-left Figure: total doseof 48 Gy), and FIG. 2 on the lower right is an image showing theblood-flow signals in the tumor one week after the end of theradiotherapy.

FIG. 3 shows an example of the use of the radiosensitizer of Example 3.FIG. 3 on the left is an image showing the right side of the patient'schest, from the thorax to the neck region, FIG. 3 on the upper right isa coronal image of the part obtained by computerized tomography (CT),and FIG. 3 on the lower right is a PET-CT frontal image of the patient.

FIG. 4 shows the effect of the radiosensitization method conducted inExample 3. FIG. 4 on the upper left is a CT image of the neck area priorto radiotherapy, and FIG. 4 on the lower left is a CT image of the rightaxilla prior to radiotherapy. FIG. 4 on the upper right is a CT imagetaken after the neck has been irradiated seven times (total dose of19.25 Gy) without injecting a radiosensitizer, and FIG. 4 on the lowerright is a CT image taken after the right axilla has been injected witha radiosensitizer and irradiated seven times (total dose of 19.25 Gy).

FIG. 5 shows the effect of the anti-cancer chemotherapy sensitizationconducted in Example 4. The left side shows a CT image taken prior toanti-cancer chemotherapy sensitization, and the right side shows a CTimage taken after anti-cancer chemotherapy sensitization.

FIG. 6 shows the effect of the anti-cancer chemotherapy sensitizationconducted in Example 4. The left side shows a CT image taken prior toanti-cancer chemotherapy sensitization, and the right side shows a CTimage taken after anti-cancer chemotherapy sensitization.

1. A radiosensitizer or anti-cancer chemotherapy sensitizer comprising acombination of (a) hydrogen peroxide and (b) hyaluronic acid or a saltthereof.
 2. The radiosensitizer or anti-cancer chemotherapy sensitizeraccording to claim 1, wherein the sensitizer is in a form of acombination preparation of (a) component and (b) component mixedbeforehand.
 3. The radiosensitizer or anti-cancer chemotherapysensitizer according to claim 1, wherein the (a) component and the (b)component are mixed at time of use.
 4. The radiosensitizer oranti-cancer chemotherapy sensitizer according to claim 1, wherein thesensitizer is in an injection form or used as an injection.
 5. Theradiosensitizer or anti-cancer chemotherapy sensitizer according toclaim 1, wherein a hydrogen peroxide content in a final formulation is0.01 to 3.5 weight percent.
 6. The radiosensitizer or anti-cancerchemotherapy sensitizer according to claim 1, wherein a content of thehyaluronic acid or a salt thereof in a final formulation is 0.1 to 10weight percent.
 7. The radiosensitizer or anti-cancer chemotherapysensitizer according to claim 4, wherein the sensitizer is used byintratumoral injection into the area that is resistant to radiotherapyor resistant to anti-cancer chemotherapy.
 8. The radiosensitizer oranti-cancer chemotherapy sensitizer according to claim 1, wherein thesensitizer is used on a tumor area prior to irradiation or anti-cancerchemotherapy used in radiotherapy of a radioresistant tumor oranti-cancer chemotherapy of an anti-cancer chemotherapy resistant tumor.9. The radiosensitizer according to claim 8, wherein the irradiation isperformed using an X-ray beam or electron beam from a linearaccelerator.
 10. A radiotherapy or anti-cancer chemotherapy sensitizingmethod comprising a step of processing a tumor area with theradiosensitizer or anti-cancer chemotherapy sensitizer according to anyone of claims 1 to 6, at the same time as or prior to irradiation oranti-cancer chemotherapy in the course of radiotherapy or anti-cancerchemotherapy of a tumor.
 11. The sensitizing method according to claim10, wherein the tumor is resistant to radiotherapy or resistant toanti-cancer chemotherapy.
 12. The sensitizing method according to claim10, wherein the processing is conducted by an intratumoral injection ofthe radiosensitizer or anti-cancer chemotherapy sensitizer.
 13. Thesensitizing method according to claim 10, wherein the irradiation isperformed using an X-ray beam or electron beam from a linearaccelerator.
 14. The sensitizing method according to claim 10, whereinthe anti-cancer chemotherapy is conducted by administering ananti-cancer agent to a patient.
 15. A radiosensitization method oranti-cancer chemotherapy sensitization method comprising (1) a step ofprocessing a tumor area with the radiosensitizer or anti-cancerchemotherapy sensitizer according to any one of claims 1 to 6 and (2) astep of exposing the processed tumor area to irradiation or the patientto anti-cancer chemotherapy.
 16. The radiosensitization method oranti-cancer chemotherapy sensitization method according to claim 15,wherein the tumor is resistant to radiotherapy or resistant toanti-cancer chemotherapy.
 17. The radiosensitization method oranti-cancer chemotherapy sensitization method according to claim 15,wherein the processing is conducted by an intratumoral injection of theradiosensitizer or anti-cancer chemotherapy sensitizer.
 18. Theradiosensitization method or anti-cancer chemotherapy sensitizationmethod according to claim 15, wherein the irradiation is performed usingan X-ray beam or electron beam from a linear accelerator.
 19. Theradiosensitization method or anti-cancer chemotherapy sensitizationmethod according to claim 15, wherein the anti-cancer chemotherapy isconducted by administering an anti-cancer agent to a patient.
 20. Use ofthe radiosensitizer or anti-cancer chemotherapy sensitizer according toany one of claims 1 to 6 for sensitizing radiotherapy or for sensitizinganti-cancer chemotherapy.
 21. (canceled)